Following viral infections, the first line of defense consists of a highly organized and aggressive innate immune response, while the adaptive immune response, lagging behind, only develops in the context of an active innate immunity. While we have gained extensive knowledge regarding the mechanisms that determine the specificity of the adaptive immune response, very little is known about the mechanisms that determine the recognition of HIV-1 by the innate immune response. However, not only is the innate immune response critical in viral containment at a time when the adaptive immune response is just developing, it is also critical in shaping the function of the subsequent adaptive immune response. Therefore comprehensive studies aimed at deconstructing this early critical arm of the immune response, and its relationship to the adaptive immune response, are necessary to begin to more globally understand the correlates of protective immunity. Since the initial description of pattern recognition receptors, including Toll-like Receptors (TLRs), it has become more and more apparent that these receptors play a crucial role in "sensing" viral infections and initiating the innate immune response directed at the pathogen, and we provide new data demonstrating that HIV-1 encodes for several TLR7/8 ligands. Furthermore, the main cytotoxic effector cells of the innate immune response, NK cells, can specifically recognize virally infected cells via a number cell-specific receptors expressed on their surface. The aim of this proposal is to study the mechanisms by which the effector cells of the innate immune system, and in particular dendritic cells and NK cells, recognize HIV-1 infection and shape the function of the ensuing adaptive antiviral immune response. The following specific aims will be addressed: 1. Assessment of the initiation of the innate immune response by HIV-1-encoded Toll-like receptor ligands, and the impact of innate immune activity on antiviral Tcell function. 2. Determine the recognition of HIV-1-infected cells by receptors expressed on NK cells in the acute phase of infection. These studies, which will focus on the recognition of HIV-1 infection by the innate immune system, will provide crucial new insights into HIV-1 pathogenesis, and the earliest events that occur during acute HIV-1 infection that shape the adaptive immune response. The studies assessing the impact of innate immune activation on the quality of the ensuing adaptive virus-specific immune response will furthermore by directly relevant for HIV-1 vaccine design.